The main objective of this program project is to determine how structural changes in the cerebral vasculature affect brain function and behavior in elderly persons. The knowledge and understanding obtained from this project is intended to provide a solid base for developing effective treatment for highly prevalent and clinically significant disorders. Various changes in the cerebral vasculature (atherosclerosis, arteriosclerosis, amyloid angiopathy) will be systematically quantified in Project 4. The pathophysiology of chronic ischemia, which may play a particularly important role in persons with slowly progressive cognitive decline, will be examined in project 3. The metabolic, physiologic, and behavioral correlates of lacunar infarction and deep white matter changes will be investigated in projects 1, 2, and 3. Finally, questions related to natural history, clinico-pathologic correlation and diagnosis are addressed jointly by three Cores. The relationship between vasculature, ischemia, and behavior is complex; understanding requires a comprehensive inter-disciplinary approach. The program project represents a multi-institutional collaborative effort involving investigators at the University of Southern California and the University of California at Irvine, Los Angeles, San Francisco and Davis. Clinical recruitment and longitudinal follow-up will take place at 6 Alzheimer Disease Diagnostic and Treatment Centers (ADDTC) supported by the State of California. Whenever possible, provisions have been made to share resources (such as patients, protocols, data, and tissues) across the program. From both a thematic and logistical standpoints, we have attempted to create a highly-cohesive and cost-effective research program.